This application addresses broad Challenge Area (15) Translational Research and specific Challenge Topic 15-OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. This Challenge Grant application is focused on arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare primary heart muscle disorder characterized by a high incidence of serious ventricular tachyarrhythmias and sudden cardiac death, typically preceding the development of contractile dysfunction and cardiac remodeling1, 2. It is the most arrhythmogenic form of human heart disease. The rate of appropriate ICD shocks in patients with ARVC greatly exceeds that for other cardiomyopathies and the ion channelopathies. Understanding the underlying determinants of arrhythmogenesis in ARVC may, therefore, provide new insights into mechanisms of sudden death in more common forms of heart disease. ARVC is a familial disease. Mutations in one or more genes encoding desmosomal proteins (desmoglein, desmocollin, desmoplakin, plakoglobin, plakophilin) can be identified in at least 40% of affected individuals1, 2. As yet undiscovered mutations in other genes encoding proteins related to the structural and signaling roles of desmosomal proteins presumably account for many if not all of the remaining cases. Compared to other familial non-ischemic cardiomyopathies, ARVC is characterized by far greater variability in genetic penetrance and disease manifestation1. It is not unusual for individuals within the same family who harbor the same disease- causing mutation to have dramatically different manifestations of disease. An index case may experience sudden cardiac death at a young age whereas a first degree relative with the same mutation may appear entirely normal and survive to old age. This indicates that powerful modifiers act to determine disease expression and risk of sudden death. However, virtually nothing is known about these modifiers. Furthermore, the only effective treatment for ARVC is an implantable cardiac defibrillator which although potentially lifesaving, is expensive and can be associated with significant impact on morbidity and quality-of-life. Identification of determinants of disease expression in ARVC could provide new mechanism-based therapies1, 2. In this Challenge Grant Application, we propose to use zebrafish as a model system to discover determinants of arrhythmogenesis and disease expression in ARVC. Although fish have 2-chambered hearts, the same fundamental biological principals, developmental pathways, genetic expression profiles, and cellular structure and function properties apply to the cardiac myocytes and myocardial tissues of fish and humans3. Virtually all of the major drugs used to treat heart disease in patients have homologous receptors, signaling cascades and physiological effects in the zebrafish heart. The great advantage of the zebrafish system is that large numbers of embryos can be rapidly screened for changes in cardiac structure and function. Well established, highly productive methods for mutagenesis and genetic screening or small molecule screening can be applied to fish embryos to identify in an unbiased, genome-wide approach new genes and/or pathways related to a specific phenotype3-5. This proposal brings together two productive investigators who share common interests and are dedicated to creating a collaboration in which extraordinary advances can be made. This is a new project. It entails entirely novel, potentially very powerful, and eminently feasible new studies. If funded, it will create new jobs and include purchase of new, US made equipment. The essential ingredients to fulfill the aims of the project are in place and there is a high likelihood that this work will spawn a major new research program. Finally, we believe this work exemplifies the ideals and goals of research on rare diseases. Not only is there potential for a direct positive impact on patients with a rare but deadly heart disease, but the proposed research will likely also uncover new insights into the leading cause of death in the US in a field that has long suffered from a paucity of rational therapeutic targets and strategies. PUBLIC HEALTH RELEVANCE: This project is designed to advance our understanding of sudden cardiac death, a major public health plague. We will study a rare heart disease that carries the greatest known risk of sudden death and use a novel model system to identify genetic and other factors that determine risk of sudden death. This will not only help families with the rare disease, but also people at risk of sudden death due to common forms of heart disease.